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Hai T Tran
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MA06 - PDL1, TMB and DNA Repair (ID 903)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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MA06.02 - Prospective Immunogenomic Profiling of Non-Small Cell Lung Cancer: Genomic and Immune Profiling Updates from Project ICON (ID 13523)
13:35 - 13:40 | Author(s): Hai T Tran
- Abstract
- Presentation
Background
Our previous work has demonstrated that higher level of genomic complexity is associated with more heterogeneous neoantigen repertoire, suppressed T cell repertoire and postsurgical relapse in localized non-small cell lung cancers (NSCLC) highlighting the complex interaction of tumor molecular and immune landscape and their impact on cancer biology and patient survival. We launched the ICON Project (Immune Genomic Profiling of NSCLC) to prospectively delineate the molecular and immune landscape of early stage NSCLC and their impact on patient survival through a multidisciplinary approach. Here we report the updated genomic and immune analyses.
a9ded1e5ce5d75814730bb4caaf49419 Method
Surgical specimens from stage I-III NSCLC were subjected to whole-exome and RNA sequencing for mutational analysis, in silico neoantigen prediction and gene expression analysis as well as T cell receptor sequencing, cytometry by time-of-flight and multiplex immunofluorescence staining.
4c3880bb027f159e801041b1021e88e8 Result
From 2016-2018, 127 patients were accrued and 50 surgical samples have undergone WES, RNAseq, TCR sequencing and immune phenotyping. Median age is 66 yrs (range: 39-86), 52% (26/50) were female and 76% (38/50) former smokers. 76% (38/50) are non-squamous carcinomas and 24% (12/50) squamous cell carcinomas. 34% have stage I disease (17/50), 30% stage II (15/50), 34% stage III (17/50) and 2% stage IV (1/50). The majority of patients had upfront surgery (45/50; 90%). With median follow-up of 19 months, 15 patients have relapsed. Median tumor mutational burden is 7.8mut/Mb and predicted neoantigen burden was 10/sample (range: 0-250). Predicted neoantigen burden is significantly correlated with tumor mutational burden (r=0.41, p=0.002). The most commonly mutated genes are TP53, KRAS, CDKN2A, PIK3CA, EGFR, BRAF, GRIN2A and ATM. C->A transversions and C->T transitions were the most common mutational subtypes. PD-1 expression and regulatory T-cell (CD4+/FoxP3+) infiltration are significantly increased in tumor tissue compared to normal tissue (p=0.003 and p=0.02 respectively), while CD3, CD8, granzyme B and CD45RO are decreased in tumor tissue compared to normal lung.
8eea62084ca7e541d918e823422bd82e Conclusion
NSCLC tumors have an immunosuppressive microenvironment compared to tumor adjacent normal lung tissues. Clinical data will be adequate to conduct genomic and immune profiling comparisons across different clinical subgroups. Mutational and neoantigen profiling are consistent with previously reported studies and correlations between molecular and immune landscapes and its impact on patient survival are ongoing.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MA23 - Early Stage Lung Cancer: Present and Future (ID 926)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 10:30 - 12:00, Room 105
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MA23.02 - Circulating Tumor DNA Analysis with a Novel Variant Classifier for Recurrence Detection in Resected, Early-Stage Lung Cancer (ID 13498)
10:35 - 10:40 | Author(s): Hai T Tran
- Abstract
- Presentation
Background
ctDNA is a blood-based biomarker with promising potential in lung cancer for minimal residual disease (MRD) assessment and early detection of recurrence. However, data regarding feasibility are limited, especially for stage I-II disease.
a9ded1e5ce5d75814730bb4caaf49419 Method
We performed longitudinal plasma ctDNA profiling of early-stage lung cancer patients (pts) that underwent resection at MD Anderson Cancer Center from Apr 2016 to Jan 2017. Plasma ctDNA was analyzed from pre-operative and multiple post-operative time points until disease recurrence. ctDNA profiling was performed using a 30kb Digital Sequencing panel (Guardant Health) covering SNVs in 21 genes and indels in 9 genes that are commonly present in lung cancer. ctDNA profiles from ~30,000 lung cancer pts were used to train a classifier to exclude non-tumor related mutations.
4c3880bb027f159e801041b1021e88e8 Result
A total of 40 pts were included in this analysis, comprised of the first 17 pts with recurrence in the longitudinal study and 23 consecutive pts without recurrence. This cohort was primarily stage I and II (15 [38%], 16 [40%]). Histology included adenocarcinoma (29 [73%]), SCC (6 [15%]), and SCLC (2 [5%]). 58% had adjuvant therapy. Median follow-up was 17.7 (3.4 – 24.5) months and median time to recurrence was 7.1 (3.4 – 16.5) months in this selected cohort. At least one ctDNA alteration was detected in 55% (21/38) of pts with evaluable pre-op samples and in 22% (8/37) of pts at 4 weeks post-op. Presence of ctDNA at 4 weeks post-op heralded eventual recurrence with 43% sensitivity and 91% specificity (75% PPV, 73% NPV) and was significantly associated with worse recurrence free survival (p=0.022, HR 6.52; 95% CI 1.3 – 32.6), while also accounting for stage. In the absence of the variant classifier, an additional 7/37 pts had non-tumor alterations detected at 4 weeks post-op with a recurrence sensitivity and specificity of 57.1% and 69.6%. ctDNA was identified in 76% (13/17) of pts prior to or at the time of recurrence. The median interval between ctDNA detection and radiographic recurrence was 91 days.
8eea62084ca7e541d918e823422bd82e Conclusion
Detection of post-op ctDNA, as early as 4 weeks after resection of early-stage lung cancer, is associated with significantly increased risk of recurrence. Accurate detection of ctDNA in this MRD setting is enabled by a highly sensitive sequencing platform that incorporates a novel variant classifier to enhance clinical specificity.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-37 - Clinical Evaluation of Plasma-Based (cfDNA) Genomic Profiling in Over 1,000 Patients with Advanced Non-Small Cell Lung Cancer (ID 14332)
16:45 - 18:00 | Presenting Author(s): Hai T Tran
- Abstract
Background
Tumor genomic information from a simple blood collection revealing actionable mutation can improve clinical outcome without the need for an invasive tissue biopsy. We report on the clinical utility of a cell-free DNA (cfDNA) next generation sequencing (NGS) blood test in our patients with non-small cell lung cancers (NSCLC) and the outcome of treatments with targeted therapies based on the reported mutations.
a9ded1e5ce5d75814730bb4caaf49419 Method
From May 2015 to February 2017, 1078 blood samples from 1011 consecutive patients with a diagnosis of NSCLC were collected and analyzed using next-generation sequencing of cfDNA with a panel of up to 70 cancer-related genes at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA) with reported sensitivity of 0.02% mutant allele fraction with high specificity (> 99.9999%) (CCR 2018 (17):3831). Patients in this retrospective study received targeted therapy as indicated by cfDNA molecular profiling. Tumor response was evaluated by RECIST V1.1 and standard clinical evaluation.
4c3880bb027f159e801041b1021e88e8 Result
From 1011 patients, 1078 cfDNA tests sent (additional follow-up tests: 1 in 64 patients and 2 in 3 patients). In 223/1011 (22%) patients had cfDNA report with at least 1 targetable mutations; with 48/223 (22%) patients meeting criteria for this retrospective review. Study population were 31 female:17 male, median age of 63 years (ranged:31-94). The rationale for the blood test included: insufficient tissue or not available (32%), addition to tissue molecular analysis (17%), alternative to tissue biopsy(10%), on-going treatment evaluation/resistance (41%). Mutations included:EGFR T790M (15), EGFR exon 19del (12), EGFR L858R (9), EGFR exon 20 insertion (4), EGFR others (1), ALK gene fusions (5) and MET exon 14 skipping (2). The median line of therapy was 2(ranged:1-7) with 28 patients receiving TKI as 1st line of therapy based on cfDNA mutations. With targeted treatments based on ctDNA results, the responses (RECIST V1.1) were: CR(3), PR(26), SD(14) and PD(4); median PFS was 8.5 months (ranged:1-26mos) for the overall population with 4 patients still receiving targeted therapy. Median PFS was 9.5 months (ranged:1-20 months) for those receiving TKI as 1st line.
8eea62084ca7e541d918e823422bd82e Conclusion
This is the largest analysis of response rates with cfDNA directed therapy in advanced NSCLC and demonstrates positive clinical outcomes in patients treated with targeted therapy based on plasma identified biomarkers.
6f8b794f3246b0c1e1780bb4d4d5dc53
